Composition comprising complex extract of coptis japonica, phellodendron chinensis, scutellaria baicalensis, gardenia jasminoides, and rheum palmatum

Abstract

The present invention relates to a composition comprising a complex extract of Coptis japonica, Phellodendron Chinensis, Scutellaria baicalensis, Gardenia jasminoides, and Rheum palmatum. The composition was confirmed to: reduce the levels of blood cholesterol, blood lipids, and blood LDL-cholesterol in patients with dyslipidemia; reduce systolic blood pressure without affecting diastolic blood pressure and pulse rate in patients with hypertension; reduce the level of pulse wave velocity (PWV), which is an indicator of arteriosclerosis, in patients with atherosclerosis, and inhibit the recurrence rate for up to 5 years in patients with cerebral infarction. Accordingly, the composition is provided as a therapeutic agent for dyslipidemia, hypertension, arteriosclerosis, or cerebral infarction. In particular, the composition is made into an encapsulated form rather than conventional decoctions, to reduce the content of geniposide, which is reported as a side effect component, and thus an optimal composition which maintains efficacy against dyslipidemia and does not cause side effects is provided.

Description

A composition comprising a complex extract of Coptis japonica, Phellodendron chinensis, Scutellaria baicalensis, Gardenia jasminoides, and Rium palmatum

[0001] The present invention relates to a composition comprising a composite extract of Coptis japonica, Phellodendron Chinensis, Scutellaria baicalensis, Gardenia jasminoides, and Rheumatum palmatum.

[0002] Dyslipidemia refers to a condition in which blood lipid levels are abnormally elevated or decreased due to an abnormality in lipid metabolism. Dyslipidemia is caused by increased biosynthesis or decreased breakdown of lipoproteins that transport cholesterol and triglycerides. Typically, dyslipidemia refers to elevated blood total cholesterol, LDL cholesterol, and triglycerides, or decreased HDL cholesterol. The main causes of dyslipidemia can be primary and secondary. Primary hyperlipidemia refers to primary hyperlipidemia caused by a high-fat diet, lack of exercise, and genetic factors. Secondary hyperlipidemia refers to hyperlipidemia caused by underlying conditions such as hypothyroidism, chronic liver disease, and nephrotic syndrome, pregnancy, and medications. Most dyslipidemias are asymptomatic and are detected through blood tests. Elevated blood triglyceride and cholesterol levels, such as dyslipidemia, can lead to other complications such as hypertension, arteriosclerosis, and cerebral infarction. Various hyperlipidemia treatments have been developed, including statins and fibrates. However, these treatments have limited therapeutic efficacy and various side effects, necessitating the development of new treatments that can be used long-term.

[0003] Hypertension is a condition in which the pressure exerted by blood within the arteries is persistently high. The diagnostic criteria for hypertension are a systolic blood pressure of 140 mmHg or higher, or a diastolic blood pressure of 90 mmHg or higher. Hypertension is associated with dyslipidemia, arteriosclerosis, cerebral infarction, myocardial infarction, heart disease, and heart failure. Treatment for hypertension primarily involves dietary modification, but if the condition persists, medication may also be used.

[0004] Atherosclerosis is a systemic disease in which cholesterol and other substances accumulate inside the blood vessel walls, narrowing the blood vessels. It is a major cause of myocardial infarction and ischemic cerebrovascular disease caused by coronary arteries. Atherosclerosis can occur in the coronary arteries (cardiovascular) that supply blood to the heart, the cerebral and carotid arteries that supply blood to the brain, the renal arteries of the kidneys, and peripheral blood vessels, causing myocardial infarction, ischemic heart disease, cerebral infarction, cerebral hemorrhage, and renal failure. The cause of atherosclerosis is not clearly known, but it has been reported to be caused by dyslipidemia such as hypercholesterolemia, high LDL cholesterol, hypertension, smoking, diabetes, and a family history of cardiovascular disease.

[0005] Stroke, also known as apoplexy, refers to localized neurological symptoms caused suddenly by abnormal cerebral blood flow. Stroke is a leading cause of death in Korea and is recognized as a dangerous condition that can leave serious aftereffects even after treatment. Stroke can be divided into cerebral infarction and cerebral hemorrhage. While both types are caused by abnormal cerebral blood flow, their symptoms and causes differ. Currently, thrombolytics are used to treat cerebral infarction. However, treatment requires arrival at a hospital within the golden window to be effective. Delays can lead to serious aftereffects or even death.

[0006] Cerebral infarction is a type of stroke that occurs when a cerebral blood vessel is occluded (a vessel that forms a blood vessel becomes blocked) and the amount of blood supplied to the brain decreases. This means that brain tissue cannot function properly, and if the decrease in cerebral blood flow continues for a certain period of time, necrosis of brain tissue (the death of a portion of the tissue or cells) begins, reaching an irreversible state. Ischemic stroke is a general term for both cerebral infarction and transient ischemic attack. Depending on the mechanism of ischemic stroke, it is classified into cerebral infarction caused by large vessel disease, cerebral infarction caused by cardiac embolism or cardiogenic cerebral infarction, small vessel disease or lacunar infarction, and cerebral infarction caused by other rare causes. If the duration is short and symptoms completely recover within 24 hours of onset, it is classified as transient ischemic attack. Existing treatments have limitations in preventing brain damage and reperfusion damage caused by cerebral infarction, so the development of new treatments to overcome this is urgent.

[0007] The purpose of the present invention is to provide a composition comprising a complex extract of Coptis japonica, Phellodendron Chinensis, Scutellaria baicalensis, Gardenia jasminoides, and Rheum palmatum as a therapeutic agent for dyslipidemia, hypertension, arteriosclerosis, oxidative stress, and cerebral infarction by confirming the effect of preventing or improving dyslipidemia, hypertension, arteriosclerosis, and cerebral infarction.

[0008] The present invention provides a composition comprising a Coptis japonica extract, a Phellodendron Chinensis extract, a Scutellaria baicalensis extract, a Gardenia jasminoides extract, and a Rheum palmatum extract.

[0009] In addition, the present invention provides a use of the composition for preventing or treating dyslipidemia, hypertension, arteriosclerosis, oxidative stress, or cerebral infarction.

[0010] According to the present invention, a composition comprising a Coptis japonica extract, a Phellodendron Chinensis extract, a Scutellaria baicalensis extract, a Gardenia jasminoides extract, and a Rheum palmatum extract reduces the levels of blood cholesterol, blood lipids, and blood LDL-cholesterol in patients with dyslipidemia, reduces systolic blood pressure without affecting diastolic blood pressure and pulse rate in patients with hypertension, reduces the level of pulse wave velocity (PWV), which is an index of arteriosclerosis, in patients with arteriosclerosis, and suppresses the recurrence rate of up to 5 years in patients with cerebral infarction. Therefore, the composition can be provided as a therapeutic agent for dyslipidemia, hypertension, arteriosclerosis, oxidative stress, or cerebral infarction.

[0011] Figure 1 shows the results of evaluating the therapeutic effect of the composition of the present invention on dyslipidemia by changes in the levels of total cholesterol (mg / dL), total lipid (mg / dL), triglyceride (mg / dL), phospholipid (mg / dL), HDL-cholesterol (mg / dL), and LDL-cholesterol (mg / dL).

[0012] Figure 2 shows the results of evaluating the effect of the composition of the present invention on ROS (reactive oxygen species) production and ROS-mediated mitochondrial dysfunction in PC12 cells.

[0013] Figure 3 shows the results of evaluating the effect of the composition of the present invention on NO release and cytotoxicity in microglial cells.

[0014] Figure 4 shows the results of evaluating the effect of the composition of the present invention on the levels of inducible NO synthase (iNOS), IL-1β, TNF-α, and COX-2 mRNA in microglial cells.

[0015] The terms used in this specification have been selected from widely used, current terms, taking into account the functions of the present invention. However, these terms may vary depending on the intentions of those skilled in the art, precedents, the emergence of new technologies, etc. Furthermore, in certain cases, terms may be arbitrarily selected by the applicant, and in such cases, their meanings will be described in detail in the relevant description of the invention. Therefore, the terms used in this invention should not be defined simply as names, but rather based on their inherent meanings and the overall content of the present invention.

[0016] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0017] Hereinafter, the present invention will be described in more detail.

[0018] The present invention provides a composition comprising a Coptis japonica extract, a Phellodendron Chinensis extract, a Scutellaria baicalensis extract, a Gardenia jasminoides extract, and a Rheum palmatum extract.

[0019] The composition is prepared by mixing 100 parts by weight of Coptis japonica extract, 100 parts by weight of Phellodendron Chinensis extract, 100 parts by weight of Scutellaria baicalensis extract, 100 parts by weight of Gardenia jasminoides extract, and 25 parts by weight of Rheum palmatum extract based on 100 parts by weight of Coptis japonica extract. In addition, the composition includes berberine, baicalin, geniposide, and Sennoside A.

[0020] In addition, the present invention provides a use of the composition for preventing or treating dyslipidemia, hypertension, arteriosclerosis, oxidative stress, or cerebral infarction.

[0021] In one embodiment, the present invention provides a pharmaceutical composition for preventing or treating dyslipidemia, comprising a Coptis japonica extract, a Phellodendron Chinensis extract, a Scutellaria baicalensis extract, a Gardenia jasminoides extract, and a Rheumatica palmatum extract. The dyslipidemia may be hyperlipidemia or hypercholesterolemia.

[0022] In addition, the present invention provides a health functional food composition for preventing or improving dyslipidemia, comprising a Coptis japonica extract, a Phellodendron Chinensis extract, a Scutellaria baicalensis extract, a Gardenia jasminoides extract, and a Rheumatism palmatum extract. The composition exhibits an effect of reducing blood cholesterol, lipid, and LDL-cholesterol levels in patients with dyslipidemia.

[0023] In another embodiment, the present invention provides a pharmaceutical composition for preventing or treating hypertension, comprising a Coptis japonica extract, a Phellodendron Chinensis extract, a Scutellaria baicalensis extract, a Gardenia jasminoides extract, and a Rheum palmatum extract.

[0024] In addition, the present invention provides a health functional food composition for preventing or improving hypertension, comprising a Coptis japonica extract, a Phellodendron Chinensis extract, a Scutellaria baicalensis extract, a Gardenia jasminoides extract, and a Rheum palmatum extract. The composition exhibits an effect of reducing systolic blood pressure in hypertensive patients, without affecting diastolic blood pressure and pulse rate.

[0025] In another embodiment, the present invention provides a pharmaceutical composition for preventing or treating arteriosclerosis, comprising a Coptis japonica extract, a Phellodendron Chinensis extract, a Scutellaria baicalensis extract, a Gardenia jasminoides extract, and a Rheum palmatum extract.

[0026] In addition, the present invention provides a health functional food composition for preventing or improving oxidative stress, comprising a Coptis japonica extract, a Phellodendron Chinensis extract, a Scutellaria baicalensis extract, a Gardenia jasminoides extract, and a Rheum palmatum extract.

[0027] In another embodiment, the present invention provides a pharmaceutical composition for preventing or treating cerebral infarction, comprising a Coptis japonica extract, a Phellodendron Chinensis extract, a Scutellaria baicalensis extract, a Gardenia jasminoides extract, and a Rheum palmatum extract.

[0028] The above cerebral infarction is at least one selected from among asymptomatic ischemic cerebral infarction, cerebral infarction due to large-artery atherosclerosis, cerebral infarction due to small vessel occlusion, cerebral infarction due to cardioembolism, cerebral infarction due to other causes (Stroke of other determined etiology), and cerebral infarction of undetermined etiology.

[0029]

[0030] The pharmaceutical composition of the present invention can be manufactured in a unit dose form or can be manufactured by placing it in a multi-dose container by formulating it using a pharmaceutically acceptable carrier according to a method that can be easily performed by a person having ordinary skill in the art to which the present invention pertains.

[0031] The pharmaceutically acceptable carriers mentioned above are those commonly used in formulations, and include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.

[0032] In the present invention, the content of the additive included in the pharmaceutical composition is not particularly limited and can be appropriately adjusted within the content range used in conventional formulations.

[0033] The above pharmaceutical composition may be formulated in the form of one or more external preparations selected from the group consisting of injectable formulations such as aqueous solutions, suspensions, emulsions, pills, capsules, granules, tablets, creams, gels, patches, sprays, ointments, ointments, lotions, liniments, pastes, and cataplasmas.

[0034] The pharmaceutical composition of the present invention may further comprise pharmaceutically acceptable carriers and diluents for formulation. The pharmaceutically acceptable carriers and diluents include, but are not limited to, excipients such as starches, sugars, and mannitol; fillers and extenders such as calcium phosphate; cellulose derivatives such as carboxymethylcellulose and hydroxypropylcellulose; binders such as gelatin, alginates, and polyvinyl pyrrolidone; lubricants such as talc, calcium stearate, hydrogenated castor oil, and polyethylene glycol; disintegrants such as povidone and crospovidone; and surfactants such as polysorbates, acetyl alcohol, and glycerol. The pharmaceutically acceptable carriers and diluents may be biologically and physiologically compatible with the subject. Examples of diluents include, but are not limited to, saline, aqueous buffers, solvents, and / or dispersion media.

[0035] The pharmaceutical composition of the present invention may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) depending on the intended method. In the case of oral administration, it may be formulated as tablets, troches, lozenges, aqueous suspensions, oily suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups, or elixirs. In the case of parenteral administration, it may be formulated as injections, suppositories, powders for respiratory inhalation, aerosols for sprays, ointments, powders for application, oils, creams, etc.

[0036] The dosage of the pharmaceutical composition of the present invention may vary depending on the patient's condition and weight, age, sex, health status, dietary constitution, nature of the formulation, severity of the disease, administration time of the composition, administration method, administration period or interval, excretion rate, and drug form, and may be appropriately selected by a person skilled in the art. For example, the dosage may range from about 0.1 to 10,000 mg / kg, but is not limited thereto, and may be administered once or several times a day in divided doses.

[0037] The pharmaceutical composition may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) depending on the intended method. The pharmaceutically effective amount and effective dosage of the pharmaceutical composition of the present invention may vary depending on the formulation method, administration method, administration time, and / or administration route of the pharmaceutical composition, and a person skilled in the art can easily determine and prescribe an effective dosage for the intended treatment. The pharmaceutical composition of the present invention may be administered once a day or divided into several doses.

[0038]

[0039] The food composition of the present invention can be generally used as a commonly used food.

[0040] The food composition of the present invention can be used as a health functional food. The term "health functional food" refers to a food manufactured and processed using raw materials or ingredients with functional properties beneficial to the human body, as defined by the Health Functional Food Act. "Functionality" refers to ingestion for the purpose of obtaining beneficial effects for health purposes, such as regulating nutrients for the structure and functions of the human body or physiological effects.

[0041] The food composition of the present invention may include conventional food additives, and its suitability as the "food additive" is determined by the specifications and standards for the relevant item in accordance with the general provisions and general test methods of the Food Additive Code approved by the Ministry of Food and Drug Safety, unless otherwise specified.

[0042] Items listed in the above "Food Additives Code" include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, high-molecular-weight pigment, and guar gum; and mixed preparations such as sodium L-glutamate preparations, alkaline agents for noodles, preservative preparations, and tar color preparations.

[0043] The food composition of the present invention can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc.

[0044] For example, among health functional foods in capsule form, hard capsules can be manufactured by mixing and filling a composition according to the present invention with additives such as excipients into a conventional hard capsule, and soft capsules can be manufactured by mixing the composition according to the present invention with additives such as excipients and filling it into a capsule base such as gelatin. The soft capsules may contain a plasticizer such as glycerin or sorbitol, a coloring agent, a preservative, etc., as needed.

[0045] The definitions of terms for the above excipients, binders, disintegrants, lubricants, flavoring agents, etc. are described in literature known in the art and include those with identical or similar functions. There are no specific restrictions on the type of food, and all health functional foods in the conventional sense are included.

[0046] As used herein, the term "prevention" refers to any action that suppresses or delays the onset of a disease by administering a composition according to the present invention. The term "treatment" refers to any action that improves or beneficially alters the symptoms of a disease by administering a composition according to the present invention. As used herein, "improvement" refers to any action that improves the worsening condition of a disease by administering or ingesting a composition according to the present invention to a subject.

[0047] Hereinafter, to aid understanding of the present invention, experimental examples and examples will be described in detail. However, the following experimental examples and examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental examples and examples of the present invention are provided to more fully explain the present invention to those of average skill in the art.

[0048]

[0049] [Example]

[0050] The composition according to the present invention exhibits a therapeutic effect on cerebrovascular and various arteriosclerotic diseases, and is effective in treating pathological inflammation of cardiovascular disease and cerebrovascular disease. To verify this, the composition of Example 1 as shown in Table 1 below was prepared, and the therapeutic effect was confirmed in patients with each disease. The composition of the present invention contains extracts of Coptis japonica, Phellodendron Chinensis, Scutellaria baicalensis, Gardenia jasminoides, and Rheumatoid arthritis (Rheum palmatum), and each extract is an ethanol (EtOH) or water extract.

[0051] Coptis japonica, Phellodendron Chinensis, Scutellaria baicalensis, Gardenia jasminoides, and Rheum palmatum were purchased from Chinese markets. Each raw material was added to 80% ethanol or distilled water and extracted twice in boiling water for 2 h. These extracts were filtered, evaporated using a rotary vacuum evaporator, and finally freeze-dried using a freeze dryer.

[0052] Ingredient Example 1 EtOH extraction yield (%) Water extraction yield (%) Coptis japonica 415.8 11.8 Phellodendron Chinensis 410.9 9.3 Scutellaria baicalensis 432.0 34.3 Gardenia jasminoides 428.3 18.3 Rheumatica palmatum 135.3 18.3

[0053] The composition according to the present invention was prepared in the form of a capsule by mixing Coptis japonica extract, Phellodendron Chinensis extract, Scutellaria baicalensis extract, Gardenia jasminoides extract, and Rheum palmatum extract in a weight ratio of 4:4:4:4:1. The capsule (300 mg) of Example 1 prepared above contained 1.6 mg of berberine chloride (C 20 H 18 ClNO4, MW: 371.81 g / mol), 4.6 mg of baicalin (C 21 H 18 O11 , MW: 446.37 g / mol), 2.2 mg of geniposide (C 17 H 24 O 10 , MW: 388.37 g / mol), and 0.06 mg of sennoside A (sennoside A, C 42 H 38 O 20 , MW: 862.74 g / mol).

[0054] Afterwards, the composition of Example 1 was manufactured in the form of capsules each containing 300 mg. In order to confirm the administration effect on patients, the administration dosage was divided into experimental group 1, which was taken before meals, twice a day (600 mg / day), experimental group 2, which was taken twice a day (1,200 mg / day), and experimental group 3, which was taken three times a day (1,800 mg / day), three times a day (1,800 mg / day).

[0055]

[0056] [Experimental Example 1] Therapeutic effect on dyslipidemia

[0057] Dyslipidemia is defined as an abnormally high level of cholesterol and lipids in the blood. Dyslipidemia is a moderate risk factor for cardiovascular and cerebrovascular diseases, such as hypertension, coronary artery disease, and ischemic stroke. Known treatments for dyslipidemia include statins, fibric acid derivatives, and bile acid sequestrants. While statins are the most effective, they have been found to cause serious side effects, including myopathy, rhabdomyolysis, and liver dysfunction.

[0058]

[0059] Experimental Example 1-1. Effects on serum lipids in hyperlipidemic patients

[0060] In order to evaluate the therapeutic effect of the composition of the present invention on dyslipidemia, the therapeutic effect was evaluated in patients diagnosed with hyperlipidemia. 34 patients (10 men, 24 women) diagnosed with hyperlipidemia by a doctor with blood total cholesterol, LDL-cholesterol, and triglyceride concentrations of 200 mg / dL, 130 mg / dL, and 200 mg / dL or higher were recruited, and administered the composition of Example 1 for 8 weeks, and then the changes in vascular indices at the 4th or 8th week were analyzed. In this experiment, experimental group 3 was administered 3 tablets at a time, 3 times a day (1,800 mg / day). Follow-up examinations were performed to analyze the changes in vascular indices at the 4th week (34 patients) and the 8th week (15 patients).

[0061] Blood Index4-week Prescription Group (n=34)8-week Prescription Group (n=15)Difference Before PrescriptionAfter PrescriptionDifference Before PrescriptionAfter PrescriptionSerum Total Cholesterol (mg / dL)249.71±31.96228.91±34.5320.79±26.15258.80±35.74238.93±40.6419.87±30.62Serum Triglyceride (mg / dL)213.74±84.26192.26±90.6621.47±93.18199.73±93.68157.53±53.2042.20±69.69Serum Total Lipid (mg / dL)762.06±91.28696.47±110.1865.59±12.71760.67±112.41687.33±102.9973.33±68.73Serum phospholipids (mg / dL)251.38±27.16230.59±26.2020.79±29.55255.87±31.00239.00±8.5216.87±20.42Serum total HDL-cholesterol (mg / dL)50.62±12.8045.71±10.864.91±7.9154.73±16.351.73±9.363.00±8.68Serum total LDL-cholesterol (mg / dL)156.34±37.50144.75±36.0611.59±30.62164.12±40.60155.69±39.728.43±33.07

[0062] As shown in Table 2 above, when the capsule manufactured as an example of the present invention was prescribed to a patient diagnosed with hyperlipidemia for 4 weeks, the serum total cholesterol level was measured as 249.71±31.96 mg / dL before the prescription, but was confirmed to decrease by about 8.3% (p<0.05) to the level of 228.91±34.53 mg / dL after the prescription, and the serum total LDL-cholesterol level was measured as 156.34±37.50 mg / dL before the prescription, but was confirmed to decrease by about 7.4% (p<0.05) to the level of 144.75±36.06 mg / dL after the prescription. In addition, when the capsule manufactured as an example of the present invention was prescribed to a patient diagnosed with hyperlipidemia for 8 weeks, the serum total cholesterol level was measured as 258.80±35.74 mg / dL before the prescription, but was confirmed to decrease by about 8.3% (p<0.05) to the level of 228.91±34.53 mg / dL after the prescription. It decreased by approximately 7.7% (p<0.05) to 238.93±40.64 mg / dL, and the serum total LDL-cholesterol level was measured as 164.12±40.60 mg / dL before prescription, but decreased by approximately 21.1% (p<0.05) to 155.69±39.72 mg / dL after prescription.

[0063]

[0064] Experimental Example 1-2. Comparison of Effects with Commercially Available Hyperlipidemia Treatments

[0065] In order to compare and evaluate the therapeutic effect of the composition of the present invention on dyslipidemia, atorvastatin (Lipitor), which is currently commercially available as a hyperlipidemia treatment agent, was compared with the composition of the present invention on dyslipidemia. ®) and the effects were compared and analyzed. After recruiting 62 patients diagnosed with hyperlipidemia, the composition of Example 1 or atorvastatin (control group) was administered, and the changes in vascular indices at 8 weeks were analyzed. In this experiment, experimental group 1 was administered 1 tablet at a time, twice a day (600 mg / day), experimental group 2 was administered 2 tablets at a time, twice a day (1,200 mg / day), and the positive control group was administered atorvastatin 1 tablet at a time, once a day (10 mg / day). The changes in vascular indices at 8 weeks were analyzed through follow-up examinations.

[0066] Blood IndexExperimental Group 1 (600 mg / day)Experimental Group 2 (1,200 mg / day)Positive Control Group (10 mg / day)Before PrescriptionAfter PrescriptionBefore PrescriptionAfter PrescriptionBefore PrescriptionAfter PrescriptionSerum Total Cholesterol (mg / dL)266.7±33.7250.0±25.3271.2±21.7246.8±34.9264.2±23.2159.3±32.9Serum Triglyceride (mg / dL)270.5±196.5179.5±81.2219.8±94.2259.3±149.4217.8±240.7121.1±78.1Serum Total Lipid (mg / dL)869.7±225.2730.9±122.6788.8±110.0797.8±150.3773.3±288.0489.1±110.0Serum phospholipids (mg / dL)274.7±40.5250.3±32.1248.6±37.0243.7±24.6249.8±35.0179.6±28.5Serum total HDL-cholesterol (mg / dL)49.0±10.049.8±11.141.9±7.546.6±10.648.5±14.047.7±10.1Serum total LDL-cholesterol (mg / dL)162.6±54.0164.3±29.2185.4±29.3148.4±48.5172.1±37.187.5±24.6

[0067] As shown in Table 3 above, the total serum cholesterol level in experimental groups 1 and 2 was found to significantly decrease from 268.1±30.2 mg / dL to 248.6±29.2 mg / dL.

[0068] Experimental Example 1-3. Efficacy and Safety in Patients with Hypercholesterolemia

[0069] In order to comparatively evaluate the therapeutic effect of the composition of the present invention on dyslipidemia, the therapeutic effect was evaluated in patients with hyperlipidemia and confirmed as hypercholesterolemia. Thirty-three patients diagnosed with hyperlipidemia by a doctor and confirmed as hypercholesterolemia with a serum total cholesterol level of 240 mg / dL were recruited as shown in Table 4 below. The changes in vascular indices at 4 and 8 weeks after administration of the composition of Example 1 or atorvastatin (positive control) were analyzed. In this experiment, Experimental Group 1 was administered 1 tablet at a time, twice a day (600 mg / day), and the positive control group was administered atorvastatin 1 tablet at a time, once a day (10 mg / day). The changes in vascular indices at 4 or 8 weeks of prescription were analyzed through follow-up examinations.

[0070] Experimental group 1 (n=21) Positive control group (n=12) Female patients 11 (52.4%) 9 (75.0%) Age (years) 54.3±8.0 59.0±57.7 Medical history (persons) Cerebral infarction 4 (19.0%) 1 (8.3%) Hypertension 6 (28.6%) 5 (41.7%) Angina 0 (2.0%) 2 (16.7%) Total cholesterol (mg / dL) 269.5±21.3 264.7±24.1

[0071] Blood indicator Experimental group 1 Positive control group Before prescription 4 weeks After 8 weeks Before prescription 4 weeks After 8 weeks Total cholesterol (mg / dL) 269.5±21.3 255.0±31.8 246.9±23.7 264.7±24.1 180.9±37.3 159.3±32.9 Total lipid (mg / dL) 832.4±190.6 806.2±261.87 69.5±163.4 780.9±300.86 94.2±5 54.0 5 11.7±130.8 Triglycerides (mg / dL)245.2±155.4251.4±216.4225.4±126.3227.8±248.6255.6±458.5121.1±78.1Phospholipid (mg / dL)267.8±34.6253.9±40.8246.9±31.2248.7±36.5209.1±65.6183.8±30.8HDL-cholesterol (mg / dL)49.2±9.745.6±9.746.4±9.746.8±13.146.9±13.947.7±10.1LDL-cholesterol (mg / dL)171.2±29.8159.1±40.0155.4±26.5151.8±32.687.6±13.983.0±22.1

[0072] As shown in Table 5 and Figure 1 above, in experimental group 1, the serum total cholesterol level was measured at 269.5±21.3 mg / dL before prescription, but decreased to 246.9±23.7 mg / dL after prescription (p<0.01), and the serum total LDL-cholesterol level was measured at 171.2±29.8 mg / dL before prescription, but decreased to 155.4±26.5 mg / dL after prescription (p<0.05).

[0073]

[0074] [Experimental Example 2] Therapeutic effect on hypertension

[0075] Hypertension is a risk factor for atherosclerotic diseases such as cerebral infarction and coronary artery disease. In order to evaluate the therapeutic effect of the composition of the present invention on hypertension, the therapeutic effect was evaluated in patients with cerebral infarction and stage 1 hypertension. Twenty-eight patients diagnosed with cerebral infarction and stage 1 hypertension were recruited as shown in Table 6 below. After administering the composition of Example 1, changes in blood pressure indices were analyzed using blood pressure monitoring (24ABPM) for 24 hours. In this experiment, experimental group 2 was administered two tablets at a time, twice a day (1,200 mg / day), and no treatment was prescribed to the control group.

[0076] Experimental group 2 (n=15) Control group (n=13) Age (years) 64.8±9.59 65.62±9.77 Male patients 8 (53.3%) 4 (30.8%) Ischemic cerebral infarction patients 12 (80%) 13 (100%) Medical history Diabetes mellitus 7 (46.7%) 2 (15.4%) Urinary tract infection 1 (6.7%) 0 (0%) Hyperlipidemia 1 (6.7%) 0 (0%) Duration after onset (days) 18.73±10.9 20.77±12.19 Baseline systolic blood pressure (mmHg) 141.37±8.96 138.71±11.36 Baseline diastolic blood pressure (mmHg) 83.36±8.75 80.61±5.44 Baseline pulse rate (bpm) 72.10±10.45 74.47±9.03

[0077] Bpm: Beats per minute

[0078] Blood Index Experimental Group 2 Control Group Prescription Difference before and after 2 weeks Prescription Difference before and after 2 weeks SBP (mmHg) 141.37±8.96 133.28±9.46 9.09±8.73 138.71±11.36 137.27±8.93 1.75±6.9 DBP (mmHg) 83.36±8.75 83.06±8.03 0.30±5.21 80.61±5.44 81.0±6.34-0.40±6.90 PR (bpm) 72.10±10.45 72.41±10.55-0.31±7.00 74.47±9.03 72.75±8.2 11.30±5.24

[0079] SBP: systolic blood pressure, DBP: diastolic blood pressure, PR: pulse rate, bpm: beat per minute.

[0080] Experimental group 2 Control group Systolic blood pressure T / P (Peak / Trough) ratio 0.87-0.87 Smoothness index 1.04-0.25 Diastolic blood pressure T / P (Peak / Trough) ratio 1.04-0.25 Smoothness index 0.05-0.06

[0081] As shown in Table 7 above, in experimental group 2, systolic blood pressure decreased from 141.37±8.96 mmHg to 132.28±9.46 mmHg after 2 weeks of prescription (p=0.03). On the other hand, in the control group, there was no significant difference from 138.71±11.36 mmHg to 132.27±8.93 mmHg. There were no significant changes in diastolic blood pressure and pulse rate. Typically, in clinical trials, a small decrease in systolic blood pressure tends to reduce the incidence of cerebral infarction. Some studies have reported that a decrease in systolic blood pressure of 10 to 12 mmHg alone reduces the risk of cerebral infarction by about 38%, and a decrease in systolic blood pressure of 3.8 mmHg contributed to a 32% decrease in the incidence of cerebral infarction. Therefore, the reduction in systolic blood pressure by prescribing the composition of the present invention from the above results proves not only the improvement of hypertension but also the improvement effect of cerebral infarction.

[0082]

[0083] [Experimental Example 3] Therapeutic Effect on Atherosclerosis

[0084] Endothelial dysfunction is a major cause of various atherosclerotic diseases, including cerebrovascular disease, cardiovascular disease, and peripheral vascular disease. Previous studies have shown that the composition of the present invention activates NOS mRNA, which plays a key role in preventing atherosclerosis. It also suppresses VCAM-1 mRNA, which is expressed in human endothelial cells, a site prone to the development of atherosclerotic lesions.

[0085] Atherosclerosis is a condition in which the elasticity of the media within blood vessels decreases. When arteriosclerosis occurs, arteries thicken and harden, restricting blood flow to organs and tissues. This can be a contributing factor to atherosclerosis and a risk factor for various cardiovascular diseases.

[0086]

[0087] Experimental Example 3-1. Effects of increased baPWV on arterial stiffness in patients

[0088] In order to evaluate the therapeutic effect of the composition of the present invention on atherosclerosis, the therapeutic effect was evaluated in patients with increased baPWV (brachial-ankle pulse wave velocity). Pulse wave velocity (PWV) is a representative indicator of atherosclerosis. 35 patients with an increase in baPWV of 1,400 cm / sec or more were recruited as shown in Table 9. The change in baPWV after administration of the composition of Example 1 was analyzed. In this experiment, experimental group 3 was administered 3 tablets at a time, 3 times a day (1,800 mg / day), and no treatment was prescribed to the control group.

[0089] Experimental group 3 (n=15) Control group (n=13) Age (years) 61.4±9.663.4±10.5 Gender Male vs Female (persons) 6 vs 144 vs 11 SBP (mmHg) 152.9±22.0147.6±25.3 DBP (mmHg) 91.3±8.089.2±8.2 PWV (cm / sec) 1736.0±271.11668.0±116.2

[0090] SBP: systolic blood pressure, DBP: diastolic blood pressure, PWV: pulse wave velocity.

[0091] PWV before prescriptionPWV after prescriptionp-valueExperimental group 31736.0±271.11599.0±301.90.032Control group 1668.3±116.21653.3±184.10.774

[0092] As shown in Table 10 above, in experimental group 3, baPWV decreased from 1736.0±271.1 cm / sec to 1599.0±301.9 cm / sec after 8 weeks of prescription (p=0.032). On the other hand, in the control group, there was no significant difference from 1668.3±116.2 cm / sec to 1653.3±184.1 cm / sec.

[0093] [Experimental Example 4] Improvement of cerebral blood flow and cerebrovascular reactivity

[0094] Cerebrovascular reactivity is an index that indicates the degree of change in cerebral arteries and cerebral blood flow in response to substances that act on the contraction or expansion of cerebral blood vessels by evaluating the dilatational capacity of blood vessels and measuring the corresponding vascular reserve capacity.

[0095] To evaluate the improving effect of the composition of the present invention on cerebral blood flow and cerebrovascular reactivity, healthy volunteers were recruited. Twelve healthy male volunteers (mean age: 26.3±1.1 years) without cerebrovascular disease, heart disease, hypertension, diabetes, thyroid disease, or psychiatric problems were recruited. The experiment was conducted as a randomized, multiple crossover experiment, and the volunteers were analyzed for changes in indices before administration (T0), 1 hour after administration (T1), 2 hours after administration (T2), and 3 hours after administration (T3) after fasting. In this experiment, experimental group 1 was administered 1 tablet twice a day (600 mg / day), and experimental group 2 was administered 2 tablets twice a day (1,200 mg / day). No treatment was prescribed to the control group.

[0096] Experimental group 1 (600 mg / day) Experimental group 2 (1,200 mg / day) Control group T0 CVR (% / min) 2.06±0.31 2.00±0.25 2.16±0.42 T1 CVR (% / min) 2.37±0.39 2.24±0.28 2.08±0.39 T2 CVR (% / min) 2.56±0.42 2.35±0.38 1.93±0.33 T3 CVR (% / min) 2.64±0.44 2.53±0.30 1.99±0.36 T0 CV40 (cm / sec) 51.4±9.49 52.2±7.34 54.7±8.77 T1 CV40 (cm / sec)52.4±10.6953.3±7.5354.3±8.87T2 CV40 (cm / sec)52.7±11.3953.5±8.8854.1±9.30T3 CV40 (cm / sec)55.2±12.9254.8±7.7052.2±9.69

[0097] CVR: cerebrovascular reactivity, CV40: corrected cerebral blood flow velocity. As shown in Table 11 above, in experimental group 1, cerebrovascular reactivity (CVR) significantly increased from 2.06±0.31 % / min to 2.64±0.44 % / min over the prescription time. In addition, in experimental group 2, cerebrovascular reactivity (CVR) significantly increased from 2.00±0.25 % / min to 2.53±0.30 % / min over the prescription time. On the other hand, no significant difference was observed in the control group.

[0098] In addition, the change in corrected cerebral blood flow velocity (CV40) was found to significantly increase from 51.4±9.49 cm / sec to 55.2±12.92 cm / sec over the prescription time in experimental group 1. In addition, it was found to significantly increase from 52.2±7.34 cm / sec to 54.8±7.70 cm / sec over the prescription time in experimental group 2. On the other hand, no significant difference was found in the control group.

[0099] Experimental group 1 (600 mg / day) Experimental group 2 (1,200 mg / day) Control group Mean blood pressure (mmHg) T0 8 2.3 ± 4.1 6 8 3.4 ± 4.7 9 8 4.5 ± 4.57 T1 8 3.6 ± 4.0 2 8 4.4 ± 5.2 5 8 4.8 ± 5.27 T2 8 2.9 ± 5.2 6 8 4.9 ± 4.0 2 8 5.4 ± 4.81 T3 8 3.4 ± 5.0 7 8 4.7 ± 4.0 9 8 5.2 ± 4.32 Heart rate (bpm) T0 6 5.2 ± 9.0 6 3.7 ± 9.2 6 6.7 ± 9.47 T1 6 5.1 ± 9.7 9 6 4.3 ± 7.7 1 6 5.6 ± 8.63 T2 6 3.7 ± 8.5863.9 ± 9.7364.8 ± 8.36T364.3 ± 7.6862.8 ± 8.6465.0 ± 9.47

[0100] bpm: beats per minutes. As shown in Table 12 above, there was no significant difference in the average blood pressure and heart rate before and after the prescription in experimental groups 1 and 2.

[0101] The above results demonstrate that the composition of the present invention improves cerebrovascular reactivity and cerebral blood flow velocity, and has a preventive effect against the recurrence of small-vessel occlusive cerebral infarction. Furthermore, the results demonstrate that the composition of the present invention does not exhibit adverse effects affecting blood pressure or heart rate.

[0102]

[0103] [Experimental Example 5] Prevention of cerebral infarction

[0104] Experimental Example 5-1. Preventing the progression of asymptomatic cerebral infarction.

[0105] In order to evaluate the recurrence prevention effect of the composition of the present invention for cerebral infarction, the recurrence prevention effect in asymptomatic cerebral infarction patients was evaluated. 31 patients diagnosed with cerebral infarction by a doctor were recruited. After administering the composition of Example 1, the occurrence of cerebral infarction and side effects were monitored for one year. In this experiment, experimental group 1 was administered twice a day, one tablet at a time (600 mg / day). As a result of the one-year monitoring, 10 subjects were lost to follow-up / withdrew midway, and 21 patients completed the follow-up. Two of the 21 patients experienced ischemic cerebral infarction, but 19 patients did not experience recurrence of cerebral infarction.

[0106]

[0107] Experimental Example 5-2. Preventive Effect on Recurrent Cerebral Infarction in Patients with Small-Blood Vessel Disease (Preliminary Study)

[0108] In order to evaluate the recurrence prevention effect of the composition of the present invention for cerebral infarction, the recurrence prevention effect in patients with small vessel occlusion (SVO) cerebral infarction was evaluated. 158 patients diagnosed with SVO cerebral infarction by a physician were recruited. After administering the composition of Example 1, the occurrence of cerebral infarction and side effects were monitored for one year. In this experiment, experimental group 1 was administered one tablet at a time, twice a day (600 mg / day). As shown in Table 13 as a result of the one-year monitoring, 73 patients out of 158 patients completed the follow-up. Of the 73 patients, 3 (4.1%) experienced a recurrence of cerebral infarction. The number of patients lost to follow-up or dropped out midway was 85, and only 54 of them were included in the final analysis. Of the 54 patients, 8 (14.8%) experienced a recurrence of cerebral infarction. The recurrence rate of ischemic cerebral infarction was confirmed to be 3.6 times higher in patients who gave up treatment compared to patients who continued treatment.

[0109] Continuing treatment group (n=73) Intermittent group (n=54) Sex Male: Female 36:37 27:27 Age (years) 63.9±8.9 63.8±9.0 History of previous cerebral infarction 9 (12.3%) 9 (16.7%) Hypertension 51 (69.9%) 33 (61.1%) Diabetes 23 (31.5%) 6 (11.1%) Hyperlipidemia 10 (13.7%) 9 (16.7%) Smoker 23 (31.5%) 22 (40.7%) Duration of medication (months) 18.3±6.5 3.1±2.6 Antiplatelet agent 15 (20.5%) 22 (40.7%) Recurrent cerebral infarction 3 (4.1%) 8 (14.8%)

[0110] Experimental Example 5-3. Preventive effect on recurrence of cerebral infarction in patients with small vessel disease (2-year observation) In order to evaluate the preventive effect of the composition of the present invention on cerebral infarction, the recurrence prevention effect on patients with SVO (small vessel occlusion) ischemic cerebral infarction was evaluated. 356 patients diagnosed with SVO ischemic cerebral infarction by a doctor were recruited. After administering the composition of Example 1, the occurrence of cerebral infarction and side effects were monitored for 2 years. In this experiment, experimental group 1 was administered 1 tablet at a time, a total of 2 times a day (600 mg / day). An antiplatelet agent was administered to the control group. As shown in Table 14 as a result of the 2-year monitoring, brain lesions occurred in only 3 patients (2.0%) in experimental group 1 that received the composition of the present invention, whereas cerebral infarction recurred in 17 patients (8.2%) in the control group. As a result of the above, it was confirmed that patients who were administered antiplatelet agents had a 4.1 times higher rate of cerebral infarction recurrence compared to patients who were administered the composition of the present invention.

[0111] Experimental group 1 (n=148) Control group (n=208) Sex Male: Female 74:74 107:10 Age (years) 64.9±8.5 64.0±11.0 Previous cerebral infarction 11 (7.4%) 10 (4.8%) Hypertension 97 (65.5%) 85 (40.9%) Diabetes 45 (30.4%) 24 (11.5%) Hyperlipidemia 10 (6.8%) 30 (14.4%) Duration of medication (months) 24.7±11.8 25.0±11.1 Smoker 3 (2.0%) 17 (8.2%)

[0112] Experimental Example 5-4. Preventive effect on recurrence of cerebral infarction in patients with small vessel disease (5-year observation) In order to evaluate the preventive effect of the composition of the present invention on recurrence of cerebral infarction, the recurrence preventive effect on patients with SVO (small vessel occlusion) ischemic cerebral infarction was evaluated. 400 patients diagnosed with SVO ischemic cerebral infarction by a doctor were recruited. After administering the composition of Example 1, the occurrence of cerebral infarction and side effects were monitored for 5 years. In this experiment, experimental group 1 was administered 1 tablet at a time, a total of 2 times a day (600 mg / day).

[0113] Characteristics 3-year follow-up (n=270) 4-year follow-up (n=233) 5-year follow-up (n=195) Sex Male: Female 137:133 119:114 97:98 Age (years) 66.7±8.5 66.9±8.3 67.1±8.5 History Previous cerebral infarction 101 (37.4%) 97 (41.6%) 90 (46.2%) Hypertension 191 (70.7%) 172 (73.8%) 147 (75.4%) Diabetes 82 (30.4%) 71 (30.5%) 62 (31.8%) Hyperlipidemia 79 (29.3%) 79 (33.9%) 71 (36.4%) Smoker 24 (8.9%) 21 (9.0%) 15 (7.7%) Family history of cerebral infarction 82 (30.4%) 71 (30.5%)67 (34.4%)Use of antiplatelet agents (persons)171 (63.3%)152 (65.2%)135 (69.2%)Aspirin128 (47.4%)112 (48.1%)101 (51.8%)Clopidogrel55 (20.4%)48 (20.6%)40 (20.5%)Duration of composition administration35.5 (3.2%)47.0 (5.4%)58.1 (8.3%)Cerebral infarction recurrence rate7 (2.6%)11 (4.7%)12 (6.2%)

[0114] As shown in Table 15 above, 270 patients completed 3-year follow-up, 233 patients completed 4-year follow-up, and 195 patients completed 5-year follow-up. Of the 270 patients who completed 3-year follow-up, 7 (2.6%) developed recurrent cerebral infarction, and of the 233 patients who completed 4-year follow-up, 4 (1.7%) developed an additional cerebral infarction, resulting in a cumulative recurrence rate of 4.7%. Of the 195 patients who completed 5-year follow-up, 1 (0.5%) developed an additional cerebral infarction, resulting in a cumulative recurrence rate of 6.2%.

[0115] Experimental Example 5-5. Preventive Effect on Recurrent Cerebral Infarction (Preliminary Study)

[0116] In order to evaluate the recurrence effect of the composition of the present invention on cerebral infarction, the effect of preventing cerebral infarction recurrence on all types of cerebral infarction was evaluated. 202 patients with cerebral infarction belonging to all types of TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification were recruited as shown in Table 16. Cerebral infarction belonging to all types of TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification includes large-artery atherosclerosis, small vessel occlusion, cardioembolism, stroke of other determined etiology, and stroke of undetermined etiology. After administering the composition of Example 1, the occurrence of cerebral infarction and side effects were monitored for 2 years. In this experiment, experimental group 1 was administered 1 tablet at a time, twice a day (600 mg / day).

[0117] Characteristics Patient information (n=202) Gender Male: Female 105: 97 Age (years) 72.94±10.63 Body mass index 24.06±2.83 Medical history Hypertension 140 (69.31%) Diabetes 63 (31.19%) Dyslipidemia 81 (40.10%) Atrial fibrillation 9 (4.46%) Other heart disease 31 (15.35%) Asymptomatic carotid artery stenosis 18 (8.91%) Symptomatic carotid artery stenosis 11 (5.45%) Current smoker 36 (17.82%) Previous cerebral infarction 33 (16.34%) Family history of cerebral infarction 36 (17.82%) TOAST classification Aortic atherosclerosis 73 (36.14%) Cardiac embolism 20 (9.90%) Small vessel occlusion 89 (44.06%) Other causes Cerebral infarction 4 (1.98%) Unexplained cerebral infarction 16 (7.92%) Antiplatelet or anticoagulant use 202 (100%) Antiplatelet agent Aspirin 122 (60.40%) Clopidogrel 86 (42.57%) Cilostazol 35 (17.33%) Ticlopidine 6 (2.97%) Triflusal 6 (2.97%) Anticoagulant Warfarin 9 (4.46%) Apixaban 5 (2.48%) Edoxaban 3 (1.49%) Rivaroxaban 6 (2.97%) Dabigatran 1 (0.50%)

[0118] 2-year follow-up results Number of patients Total cumulative number of recurrent ischemic strokes (n = 202) 9 (4.46%) Aortic atherosclerosis (n = 73) 4 (5.48%) Cardioembolism (n = 20) 1 (5.00%) Small vessel occlusion (n = 89) 1 (1.12%) Other causes of cerebral infarction (n = 4) 2 (50.0%) Unexplained causes of cerebral infarction (n = 16) 1 (6.25%) Total number of adverse events (n = 202) 0

[0119] As shown in Table 17 above, as a result of using the composition of the present invention, an antiplatelet agent, or an anticoagulant in combination for 2 years, the cumulative cerebral infarction recurrence rate was 4.46%, which was significantly lower than the cerebral infarction recurrence rate of 8% to 12% with conventional antiplatelet agents.

[0120] [Experimental Example 6] Safety and Side Effects

[0121] The most common side effect of existing antiplatelet therapy is bleeding, which can be fatal. For example, aspirin users experience 5.58 bleeding episodes per 1,000 people per year, a rate 1.55 times higher than that of non-aspirin users. To verify the occurrence of side effects and safety of the composition of the present invention, a retrospective cohort study was conducted. Clinical adverse reactions were analyzed in 656 patients who were prescribed the composition of the present invention.

[0122] Of the 656 subjects, 13 (2.0%) reported experiencing indigestion, headache, insomnia, chest discomfort, general fatigue, thirst, or gastrointestinal symptoms. These results indicate that the frequency of adverse effects occurring in statin drugs is significantly lower than that of atorvastatin (20%) and lovastatin (21%). Furthermore, no serious adverse effects, such as liver or kidney dysfunction, were observed.

[0123]

[0124] [Experimental Example 7] Analysis of changes according to mixing ratio

[0125] The change in the effective ingredient according to the mixing ratio of the composition according to the present invention was verified. The compositions of Examples 1 to 4 were prepared as shown in Table 18 below.

[0126] Ingredients Example 1 Example 2 Example 3 Example 4 Coptis japonica 4444 Phellodendron Chinensis 4444 Scutellaria baicalensis 4444 Gardenia jasminoides 4444 Rheumatica palmatum 1240

[0127] Experimental Example 7-1. Changes in the content of effective ingredients The contents of the main ingredients of the examples manufactured above were analyzed according to the quantitative method of the herbal medicine test method.

[0128] Active ingredient (% by weight) Example 1 Example 2 Example 3 Example 4 Berberine 1.6 2.07 1.97 1.59 Baicalin 4.6 4.74 4.50 4.32 Geniposide 2.2 1.99 1.91 2.49 Sennoside A 0.06 0.10 050

[0129] Berberine is extracted from Coptis japonica and Phellodendron Chinensis. Berberine has potent antibacterial, anti-inflammatory, and antidiabetic effects, and is an effective ingredient that lowers cholesterol levels and improves cardiovascular health. Baicalin is extracted from Scutellaria baicalensis. Baicalin is an effective ingredient that has anti-inflammatory, antiviral, and anticancer effects, and exhibits skin and neuroprotective effects. Geniposide is extracted from Gardenia jasminoides. Geniposide exhibits anti-inflammatory and antioxidant effects, and is useful for liver protection and diabetes treatment. The above results summarize the composition of Example 1, demonstrating that it has the most suitable combination ratio because it has a higher content of active ingredients than the other examples.

[0130]

[0131] 7-2. Changes in small intestine absorption rate

[0132] Intestinal absorption rate is an indicator of how effectively a food or drug ingredient is absorbed through the small intestine and into the body. High absorption of a drug is a key indicator of improved bioavailability, more precise dosing, fewer side effects, faster therapeutic effects, cost-effectiveness, and consistency in treatment plans. Higher bioavailability means that more of the drug is active and effective in the body. In other words, a higher absorption rate can lead to a greater therapeutic effect with the same dose. Consistently high absorption facilitates accurate dosing. This is crucial for personalized treatment, reducing side effects from overdosing and preventing treatment failure due to underdosing. Drugs efficiently absorbed from the small intestine are less likely to circulate inefficiently or accumulate in the body, reducing potential side effects and toxicity. This is particularly important for patients requiring long-term treatment. High intestinal absorption rate means that the drug is absorbed quickly and begins to act quickly. This is particularly valuable in situations requiring rapid management of acute symptoms. Effective drug absorption allows for high efficacy even with lower doses, increasing drug cost-effectiveness. This helps reduce medical costs and patient burden. High drug absorption can predict treatment plans. This plays a crucial role in allowing physicians to predict patient responses and adjust treatment plans accordingly.

[0133] The absorption rates in the small and large intestines of the above examples 1 to 4 were evaluated.

[0134] To measure the absorption rate (small intestinal transit capacity) in the small intestine, Examples 1 to 4 were orally administered to male mice that had fasted for 12 hours. Distilled water was administered to three mice as a control group. One hour after each sample was administered, 0.2 mL of 25% BaSO4 was orally administered, and 45 minutes later, the mice were sacrificed and the distance traveled by 25% BaSO4 in the small intestine was measured.

[0135] To measure the absorption rate (colon transit capacity) in the large intestine, Examples 1 to 4 were orally administered to male mice that had fasted for 12 hours. Distilled water was administered to three mice as a control group. One hour after each sample was administered, 0.2 mL of 25% BaSO4 was orally administered, and the time until feces containing 25% BaSO4 were observed was measured.

[0136] Dose (mg / kg) Small intestine absorption rate (%) Large intestine absorption rate (%) Control group - Example 175066±9162±7.5 Example 21275-147±6.1 Example 3150063±9129±10.0 Example 4120058±4174±7.2

[0137] The small intestinal absorption rate of Example 1 was 66±9%, demonstrating superiority over Examples 3 and 4. This is an important indicator for maximizing drug efficacy and providing more effective treatment outcomes for patients. A high small intestinal absorption rate allows the drug to be better absorbed in the body, enabling it to achieve the desired therapeutic effect more quickly and effectively. Therefore, the composition of Example 1, with its excellent small intestinal absorption rate, was confirmed as a drug capable of maximizing therapeutic effects.

[0138] [Experimental Example 8] In vitro experiment on protection against ROS-mediated mitochondrial dysfunction

[0139] A major cause of neuronal cell death is the increase in reactive oxygen species (ROS), which trigger an inflammatory response and impair mitochondrial function. The toxic effects of ROS disrupt mitochondrial membrane permeability, translocate Bcl-2 proteins, and increase cytosolic cytochrome c levels, activating caspase-3, a key player in the signaling pathway leading to cell death. The protective effects of the composition of the present invention against ROS production and ROS-mediated mitochondrial dysfunction were investigated in vitro using a Parkinson's disease model.

[0140] As shown in Fig. 2, when PC12 cells were treated with 100 μM 6-OHDA (6-hydroxydopamine), the ROS concentration significantly increased by 158.49 ± 1.76% compared to the control group. On the other hand, it was confirmed that pretreatment with the composition (NRX) of the present invention alleviated the increase in ROS production, and when pretreated with 10 μg / ml and 100 μg / ml, the ROS levels were 135.59 ± 1.20% and 129.91 ± 1.80% compared to the control group. In addition, the change in the activity of caspase-3 involved in the apoptosis signal transduction pathway was analyzed. When PC12 cells were treated with 6-OHDA for 6 hours, the activity of caspase-3 was found to significantly increase by 181.94 ± 16.44% compared to the control group. On the other hand, it was confirmed that the tendency of increasing activity of caspase-3 was alleviated when the composition (NRX) of the present invention was pretreated, and when pretreated with 10 μg / ml and 100 μg / ml, respectively, the activity of caspase-3 was 100.64±4.66% and 108.22±4.70% compared to the control group.

[0141] The above results demonstrate that the composition of Example 1 of the present invention has an effect of alleviating oxidative stress.

[0142]

[0143] [Experimental Example 9] Effect on inhibition of NO release

[0144] Microglia play a crucial role in the immune and inflammatory response of the central nervous system (CNS) and restore CNS homeostasis when activated in neuropathological conditions. Activated microglia can promote neuronal damage by releasing inflammatory and cytotoxic factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, nitric oxide (NO), and reactive oxygen species (ROS). Therefore, chronic microglial activation has been linked to various neuronal destructions, including stroke and neurodegenerative diseases. We evaluated whether the composition of the present invention inhibits NO release. As shown in Fig. 3, the composition (NRX) of the present invention was confirmed to inhibit NO release from LPS-induced microglia in a concentration-dependent manner. Furthermore, cell viability was confirmed using an MTT assay, and it was found that cell viability did not change despite increasing the treatment dose of the composition (NRX) of the present invention.

[0145] In addition, the range of anti-inflammatory action of the composition of the present invention on microglial activation was evaluated. Rat brain microglial cells were stimulated with LPS, and the levels of inducible nitric oxide synthase (iNOS), IL-1β, TNF-α, and COX-2 mRNA were measured. As shown in Fig. 4, the levels of inducible nitric oxide synthase (iNOS), IL-1β, TNF-α, and COX-2 mRNA significantly increased by LPS stimulation, but the increased levels of iNOS, IL-1β, TNF-α, and COX-2 mRNA were found to decrease when the composition of the present invention (NRX) was treated.

[0146]

[0147] [Experimental Example 10] LC-MS / MS Analysis

[0148] To establish a profile of the indicative components of the composition according to the present invention, molecular weights were determined through LC-MS / MS analysis. Berberine, Baicalin, and Geniposide, the substances believed to have major pharmacological activity, were dissolved in the same solvent, DMSO, to a concentration of 10,000 ppm, and then diluted with methanol to a final concentration of 5,000 ppm.

[0149] Lipid chromatography analysis was performed using an Agilent 1290 Infinity LC System (Agilent Technologies, Santa Clara, CA, USA) using a Waters C18 column (2.1 mm × 100 mm, 1.7 μm) at 30°C. Gradient elution was performed using distilled water (A) containing 0.1% formic acid and acetonitrile (B) containing 0.1% formic acid as the mobile phase.

[0150] The mass spectrometer system was connected to an Agilent 6550 Accurate-Mass Q-TOF (Agilent Technologies, Santa Clara, CA, USA) equipped with dual Agilent Jet Stream Technology Electrospray Ionization (AJS ESI) sources, and analyses were performed in positive and negative ion modes. Data analysis for compound profiling was performed using MassHunter Qualitative Analysis Software (version B.07.00, Agilent Technologies, Santa Clara, CA, USA).

[0151] As a result of the LC / MS test, as shown in Figure 5, it was confirmed that the geniposide content (peak (2) of a) of the composition according to the present invention was significantly reduced compared to the standard peak (b) of geniposide.

[0152] In addition, based on Figure 5, the content (100 mg) of geniposide of the present invention was confirmed to be 0.597%.

[0153] Figure b shows that the standard 100 ppm area is 25,161,180.66,

[0154] Figure a shows that the area corresponding to 100 ppm of the sample is 150,120.24,

[0155] 100 ppm equivalent area of ​​sample = 7,506,011.96 × (100 / 5,000)

[0156] = 7,506,011.96 × 0.02

[0157] = 150,120.24

[0158] Relative content = (sample area / standard area) × 100%

[0159] = (150,120.24 / 25,161,180.66) × 100%

[0160] = 0.597%

[0161]

[0162] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions merely represent preferred embodiments and are not intended to limit the scope of the present invention. In other words, the substantial scope of the present invention is defined by the appended claims and their equivalents.

[0163] Numerical ranges are inclusive of the values ​​defined in the ranges above. Any maximum numerical limitation given throughout this specification includes any lower numerical limitation, as if that lower numerical limitation were explicitly stated. Any minimum numerical limitation given throughout this specification includes any higher numerical limitation, as if that higher numerical limitation were explicitly stated. Any numerical limitation given throughout this specification will include any better numerical range within the broader numerical range, as if that narrower numerical limitation were explicitly stated.

Claims

A pharmaceutical composition for preventing or treating dyslipidemia comprising an extract of Coptis japonica, an extract of Phellodendron Chinensis, an extract of Scutellaria baicalensis, an extract of Gardenia jasminoides, and an extract of Rheumatoid arthritis. A pharmaceutical composition for preventing or treating dyslipidemia, characterized in that in claim 1, the composition is prepared by mixing 100 parts by weight of a Phellodendron Chinensis extract, 100 parts by weight of a Scutellaria baicalensis extract, 100 parts by weight of a Gardenia jasminoides extract, and 25 parts by weight of a Rheum palmatum extract based on 100 parts by weight of a Coptis japonica extract. A pharmaceutical composition for preventing or treating dyslipidemia, characterized in that the dyslipidemia in claim 1 is hyperlipidemia or hypercholesterolemia. A pharmaceutical composition according to claim 1, characterized in that the composition comprises berberine, baicalin, geniposide, and Sennoside A. A health functional food composition for preventing or improving dyslipidemia, comprising a Coptis japonica extract, a Phellodendron Chinensis extract, a Scutellaria baicalensis extract, a Gardenia jasminoides extract, and a Rheum palmatum extract. In the fifth aspect, the composition is a health functional food composition for preventing or improving dyslipidemia, characterized in that it reduces the levels of blood cholesterol, lipids, and LDL-cholesterol. A pharmaceutical composition for preventing or treating hypertension, comprising an extract of Coptis japonica, an extract of Phellodendron Chinensis, an extract of Scutellaria baicalensis, an extract of Gardenia jasminoides, and an extract of Rheumatoid arthritis. A health functional food composition for preventing or improving hypertension, comprising an extract of Coptis japonica, an extract of Phellodendron Chinensis, an extract of Scutellaria baicalensis, an extract of Gardenia jasminoides, and an extract of Rheum palmatum. A health functional food composition for preventing or improving hypertension, characterized in that in claim 8, the composition reduces systolic blood pressure and does not affect diastolic blood pressure and pulse rate. A pharmaceutical composition for preventing or treating arteriosclerosis comprising an extract of Coptis japonica, an extract of Phellodendron Chinensis, an extract of Scutellaria baicalensis, an extract of Gardenia jasminoides, and an extract of Rheumatism palmatum. A health functional food composition for preventing or improving arteriosclerosis comprising a Coptis japonica extract, a Phellodendron Chinensis extract, a Scutellaria baicalensis extract, a Gardenia jasminoides extract, and a Rheum palmatum extract. A pharmaceutical composition for preventing or treating cerebral infarction comprising an extract of Coptis japonica, an extract of Phellodendron Chinensis, an extract of Scutellaria baicalensis, an extract of Gardenia jasminoides, and an extract of Rheum palmatum. In claim 12, the cerebral infarction is at least one selected from among asymptomatic ischemic cerebral infarction, cerebral infarction due to large-artery atherosclerosis, cerebral infarction due to small vessel occlusion, cerebral infarction due to cardioembolism, cerebral infarction due to other determined etiology, and cerebral infarction of undetermined etiology, a pharmaceutical composition for preventing or treating cerebral infarction. A health functional food composition for preventing or improving cerebral infarction, comprising an extract of Coptis japonica, an extract of Phellodendron Chinensis, an extract of Scutellaria baicalensis, an extract of Gardenia jasminoides, and an extract of Rheum palmatum. In any one of the first, fifth, seventh, eighth, tenth, eleventh, twelfth and fourteenth clauses, The composition is a capsule containing a mixture of a Coptis japonica extract, a Phellodendron Chinensis extract, a Scutellaria baicalensis extract, a Gardenia jasminoides extract, and a Rheum palmatum extract in a weight ratio of 4:4:4:4:1, wherein 300 mg of the capsule contains 1.6 mg of berberine chloride, 4.6 mg of baicalin, 2.2 mg of geniposide, and 0.06 mg of sennoside A.

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